Iduronate 2-sulfatase (I2S) is a lysosomal enzyme having an activity to hydrolyze a sulfate ester bond in a glycosaminoglycan molecule such as heparan sulfate and dermatan sulfate. Patients of Hunter's syndrome genetically lack I2S activity. Lack of this enzyme causes abnormal metabolism of heparan sulfate and dermatan sulfate, which then leads to accumulation of fragments of the latter molecules in tissues such as the liver and kidney, and also to excretion of heparan sulfate and dermatan sulfate in urine. These abnormalities then cause diverse symptoms in patients suffering Hunter's syndrome, including skeletal deformities and severe mental retardation.
The fact that the patients suffering Hunter's syndrome show scarce I2S activity has already been known since 1970's, and an abnormality of I2S gene was expected to be the cause of this disease. In 1999, human gene encoding I2S was isolated and confirmed to be the responsible gene for this disease (see LPL 1).
Based on the fact mentioned above, I2S replacement has been attempted since 1970's to improve the clinical conditions of the patients, including transplantation of normal macrophage (see LPL 2) and infusion of normal serum (see LPL 3) to supplement I2S activity in the patients. The results of those attempts showed that the concentration of heparan sulfate in patients' urine decreased by the supplementation of I2S activity, suggesting that I2S replacement therapy should have a clinical efficacy against Hunter's syndrome, though improvement in clinical symptoms was not confirmed. Practical application of the I2S replacement therapy, however, has been extremely limited due to the lack of supply of this enzyme.
Isolation of the gene encoding I2S in 1999 made it possible to produce I2S in a large scale using recombinant technology, and to use this enzyme as a medicament for the enzyme replacement therapy for Hunter's syndrome (see PTL 1). However a method has not been reported so far for providing I2S with such a high purity as is sufficient for the enzyme to be directly used as a medical drug.